Compositions of descarboethoxyloratadine

ABSTRACT

Methods are disclosed utilizing DCL, a metabolic derivative of loratadine, for the treatment of allergic rhinitis, and other disorders, while avoiding the concomitant liability of adverse side-effects associated with other non-sedating antihistamines.

This is a division, of application Ser. No. 08/783,393, filed Jan. 13,1997, now U.S. Pat. No. 5,731,319, which is a divisional of applicationSer. No. 08/366,651, filed Dec. 30, 1994, now U.S. Pat. No. 5,595,997.

1. BACKGROUND OF THE INVENTION

The methods of the present invention comprise administering atherapeutically effective amount of a metabolic derivative ofloratadine. Chemically, this derivative is8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridineand known as descarboethoxyloratadine (DCL). This compound isspecifically described in Quercia, et al. Hosp. Formul., 28: 137–53(1993) and U.S. Pat. No. 4,659,716.

Loratadine is an antagonist of the H-1 histamine receptor protein. Thehistamine receptors H-1 and H-2 are two well-identified forms. The H-1receptors are those that mediate the response antagonized byconventional antihistamines. H-1 receptors are present, for example, inthe ileum, the skin, and the bronchial smooth muscle of man and othermammals.

Loratadine binds preferentially to peripheral rather than to central H-1receptors. Quercia et al., Hosp. Formul. 28: 137–53 (1993). Loratadinehas been shown to be a more potent inhibitor of serotonin-inducedbronchospasm in guinea pigs than terfenadine. Id. at 137–38. Itsanti-allergenic activity in animal models was shown to be comparable tothat of terfenadine and astemizole. Id. at 138. However, using standardanimal model testing, on a milligram by milligram basis, loratadine wasshown to be four times more potent than terfenadine in the inhibition ofallergic bronchospasm. Id. Moreover, loratadine's antihistaminicactivity was demonstrated in humans by evaluation of the drug's abilityto suppress wheal formation. Id. Clinical trials of efficacy indicatedthat loratadine is an effective H-1 antagonist. See Clissold et al.,Drugs 37: 42–57 (1989).

Through H-2 receptor-mediated responses, histamine stimulates gastricacid secretion in mammals and the chronotropic effect in isolatedmammalian atria. Loratadine has no effect on histamine-induced gastricacid secretion, nor does it alter the chronotropic effect of histamineon atria. Thus, loratadine has no apparent effect on the H-2 histaminereceptor.

Loratadine is well absorbed but is extensively metabolized. Hilbert, etal., J. Clin. Pharmacol. 27: 694–98 (1987). The main metabolite, DCL,which has been identified, is reported to be pharmacologically active.Clissold, Drugs 37: 42–57 (1989). It is also reported as havingantihistaminic activity in U.S. Pat. No. 4,659,716. This patentrecommends an oral dosage range of 5 to 100 mg/day and preferably 10 to20 mg/day.

Loratadine's efficacy in treating seasonal allergic rhinitis iscomparable to that of terfenadine. Quercia et al., Hosp. Formul. 28:137, 141 (1993). Loratadine also has a more rapid onset of action thanastemizole. Id.

Clissold et al., Drugs 37: 42, 50–54 (1989) describes studies showingloratadine as effective for use in seasonal and perennial rhinitis,colds (with pseudoephedrine), and chronic urticaria. It has also beensuggested that loratadine would be useful for the treatment of allergicasthma. Temple et al. Prostaglandins 35:549–554 (1988).

Loratadine may also be useful for the treatment of motion sickness andvertigo. Some antihistamines have been found to be effective for theprophylaxis and treatment of motion sickness. See Wood, Drugs, 17:471–79 (1979). Some antihistamines have also proven useful for treatingvestibular disturbances, such as Meniere's disease, and in other typesof vertigo. See Cohen et al., Archives of Neurology, 27: 129–35 (1972).

In addition, loratadine may be useful in the treatment of diabeticretinopathy and other small vessel disorders associated with diabetesmellitus. In tests on rats with streptozocin-induced diabetes, treatmentby antihistamines prevented the activation of retinal histaminereceptors which have been implicated in the development of diabeticretinopathy. The use of antihistamines to treat retinopathy and smallvessel disorders associated with diabetes mellitus is disclosed in U.S.Pat. No. 5,019,591.

It has also been suggested that loratadine, in combination withnon-steroidal antiinflammatory agents or other non-narcotic analgesics,would be useful for the treatment of cough, cold, cold-like and/or flusymptoms and the discomfort, pain, headache, fever, and general malaiseassociated therewith. Such compositions used in the methods of treatingthe above-described symptoms may optionally include one or more otheractive components including a decongestant (such as pseudoephedrine), acough suppressant/antitussive (such as dextromethorphan) or anexpectorant (such as guaifenesin).

Many antihistamines cause adverse side-effects. These adverseside-effects include, but are not limited to, sedation, gastrointestinaldistress, dry mouth, constipation or diarrhea. Loratadine has been foundto cause relatively less sedation as compared with other antihistamines.Moreover, the incidence of fatigue, headache, and nausea was similar tothose observed for terfenadine. See Quercia et al., Hosp. Formul. 28:137, 142 (1993).

Furthermore, compounds within the class of non-sedating antihistamines,including loratadine, astemizole, and terfenadine, have been known tocause other severe adverse electrophysiologic side-effects. Theseadverse side-effects are associated with a prolonged QT interval andinclude but are not limited to ventricular fibrillation and cardiacarrhythmias, such as ventricular tachyarrhythmias or torsades depointes. Knowles, Canadian Journal Hosp. Pharm., 45: 33, 37 (1992);Craft, British Medical Journal, 292: 660 (1986); Simons et al., Lancet,2: 624 (1988); and Unknown, Side Effects of Drugs Annual, 12: 142 and14: 135.

Quercia et al., Hosp. Formul. 28: 137, 142 (1993) noted that seriouscardiovascular adverse side-effects, including torsades de pointes andother ventricular arrhythmias, were reported in “healthy” patients whoreceived terfenadine concurrently with either ketoconazole orerythromycin. Quercia et al., also states that arrhythmias have alsobeen reported with the concomitant administration of astemizole anderythromycin or erythromycin plus ketoconazole. Thus, he cautionsagainst using loratadine concurrently with ketoconazole, itraconazole,and macrolides, such as erythromycin.

Additionally, it is also known that ketoconazole and/or erythromycininterfere with cytochrome P450, and thereby inhibit the metabolism ofnon-sedative antihistamines such as terfenadine and astemizole. Becauseof the interference with the metabolism of loratadine, there exists agreater potential for adverse interaction between loratadine or othernon-sedating antihistamines and drugs known to inhibit cytochrome P450,such as but not limited to ketoconazole, itraconazole, and erythromycin.

In Brandes et al., Cancer Res. (52) 3796–3800 (1992), Brandes showedthat the propensity of drugs to promote tumor growth in vivo correlatedwith potency to inhibit concanavalin A stimulation of lymphocytemitogenesis. In Brandes et al., J. Nat'l Cancer Inst., 86:(10) 771–775(1994), Brandes assessed loratadine in an in vitro assay to predictenhancement of in vivo tumor growth. He found that loratadine andastemizole were associated with growth of both melanoma and fibrosarcomatumors. The dose for loratadine in this study was 10 mg/day.

None of the above references teach or enable the methods of the presentinvention comprising administering DCL to a human while avoiding adverseside-effects associated with the administration of other non-sedatingantihistamines; nor do the references alone or in combination suggestthese methods. Thus, it would be particularly desirable to find methodsof treatment with the advantages of known non-sedating antihistamineswhich would not have the aforementioned disadvantages.

2. SUMMARY OF THE INVENTION

It has now been discovered that DCL is an effective, non-sedatingantihistamine which is useful in treating allergic rhinitis in a human,while avoiding adverse side-effects normally associated with theadministration of other compounds within the class of non-sedatingantihistamines such as loratadine, astemizole, and terfenadine. Suchadverse side-effects include, but are not limited to, cardiacarrhythmias, cardiac conduction disturbances, fatigue, headache,gastrointestinal distress, appetite stimulation, weight gain, dry mouth,and constipation or diarrhea.

Furthermore, DCL is useful for treating allergic rhinitis while avoidingtumor promotion associated with loratadine and other non-sedatingantihistamines. Thus, this invention also relates to novel methods oftreating allergic rhinitis in a human having a higher than normalpropensity for or incidence of cancer.

Furthermore, it has now also been discovered that DCL, is useful intreating allergic asthma in a human, while avoiding the adverseside-effects associated with the administration of other non-sedatingantihistamines. As stated above, examples of such side-effects areappetite stimulation, weight gain, tumor promotion, cardiac arrhythmias,and cardiac conduction disturbances. Thus, this invention also relatesto novel methods of treating allergic asthma in a human having a higherthan normal propensity for or incidence of cancer.

In addition, DCL is useful in treating such disorders in a human asretinopathy and small vessel disorders associated with diabetes mellituswhile avoiding the adverse side-effects associated with administrationof other non-sedating antihistamines and while avoiding tumor promotionassociated with the administration of loratadine and other non-sedatingantihistamines. Thus, this invention also relates to novel methods oftreating retinopathy and small vessel disorders associated with diabetesmellitus, in a human having a higher than normal propensity for orincidence of cancer.

It has also been discovered that DCL, in combination with non-steroidalantiinflammatory agents or other non-narcotic analgesics, is useful forthe treatment of cough, cold, cold-like and/or flu symptoms and thediscomfort, pain, headache, fever, and general malaise associatedtherewith in a human, while avoiding the adverse-side-effects associatedwith the administration of other non-sedating antihistamines. The use ofsuch pharmaceutical compositions, containing DCL, and non-narcoticanalgesics or non-steroidal antiinflammatory agents such as aspirin,acetaminophen or ibuprofen, may optionally include one or more otheractive components including a decongestant (such as pseudoephedrine), acough suppressant/antitussive (such as dextromethorphan) or anexpectorant (such as guaifenesin).

The present invention also involves the use of the above-describedcompositions to treat the above-described conditions while avoidingtumor promotion associated with loratadine and other non-sedatingantihistamines. Thus, the present invention also relates to the use ofthese compositions to treat such conditions in a human having a higherthen normal propensity for or incidence of cancer.

The present invention also relates to a method of avoiding interactionbetween DCL and a drug that inhibits cytochrome P450 including but notlimited to ketoconazole, itraconazole, erythromycin, and others known bythose skilled in the art, while treating allergic rhinitis, allergicasthma, diabetic retinopathy and other small vessel disorders due todiabetes.

This invention is also directed to a method of avoiding interactionbetween DCL and a drug that inhibits cytochrome P450 including but notlimited to ketoconazole, itraconazole, erythromycin, and others known tothose skilled in the art, while treating cough, cold, cold-like and/orflu symptoms and the discomfort, headache, pain, fever and generalmalaise associated therewith, in a human, which comprises administeringa composition to said human, said composition comprising DCL and anon-steroidal antiinflammatory agent or non-narcotic analgesic. Theaforementioned compositions may optionally contain one or more otheractive components including a decongestant, coughsuppressant/antitussive, or expectorant.

It has also been discovered that DCL is useful in treating otherallergic disorders related to its activity as an antihistamine,including but not limited to, urticaria and symptomatic dermographism,in a human, while avoiding the adverse side-effects associated with theadministration of other non-sedating antihistamines and/or whileavoiding tumor promotion associated with the administration ofloratadine and other non-sedating antihistamines. Thus, this inventionalso relates to novel methods of treating allergic disorders, includingbut not limited to, urticaria and symptomatic dermographism in a humanhaving a higher than normal propensity for or incidence of cancer. Thepresent invention also relates to methods of avoiding interactionbetween loratadine or other non-sedating antihistamines and a drug thatinhibits cytochrome P450 including but not limited to ketoconazole,itraconazole, and erythromycin, and others known by those skilled in theart, while treating allergic disorders, including but not limited to,urticaria and symptomatic dermographism wherein said human isadministered DCL.

3. DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of treating allergic rhinitisin a human while avoiding the concomitant liability of adverseside-effects associated with the administration of non-sedatingantihistamines, which comprises administering to said human atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof.

The present invention further encompasses a method of treating allergicasthma in a human while avoiding the concomitant liability of adverseside-effects associated with the administration of non-sedatingantihistamines, which comprises administering to said human atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof.

Also included in the present invention is a method of treatingretinopathy or other small vessel diseases associated with diabetesmellitus in a human while avoiding the concomitant liability of adverseside-effects associated with the administration of non-sedatingantihistamines, which comprises administering to said human atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof.

The present invention further encompasses a method of treating cough,cold, cold-like, and/or flu symptoms and the discomfort, headache, pain,fever, and general malaise associated therewith, in a human, whileavoiding the concomitant liability of adverse side-effects associatedwith the administration of non-sedating antihistamines, which comprisesadministering to said human a composition, said composition comprising(i) a therapeutically effective amount of DCL or a pharmaceuticallyacceptable salt thereof and (ii) a therapeutically effective amount ofat least one non-steroidal antiinflammatory agent or non-narcoticanalgesic such as acetylsalicylic acid, acetaminophen, ibuprofen,ketoprofen, and naproxen, or a pharmaceutically acceptable salt thereof.

Additionally, the present invention encompasses a method of treatingcough, cold, cold-like, and/or flu symptoms and the discomfort,headache, pain, fever, and general malaise associated therewith, in ahuman, while avoiding the concomitant liability of adverse side-effectsassociated with the administration of non-sedating antihistamines, whichcomprises administering to said human a composition, said compositioncomprising (i) a therapeutically effective amount of DCL orpharmaceutically acceptable salt thereof, and (ii) a therapeuticallyeffective amount of a decongestant such as pseudoephedrine or apharmaceutically acceptable salt thereof.

It has been found that DCL is five to seven times less active in tumorpromotion than loratadine. Thus, the present invention furtherencompasses a method of treating allergic rhinitis in a human whileavoiding the concomitant liability of tumor promotion associated withthe administration of loratadine and other non-sedating antihistamines,which comprises administering to said human a therapeutically effectiveamount of DCL or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention includes a method of treatingallergic asthma in a human while avoiding the concomitant liability oftumor promotion associated with the administration of loratadine andother non-sedating antihistamines, which comprises administering to saidhuman a therapeutically effective amount of DCL or a pharmaceuticallyacceptable salt thereof.

The present invention further encompasses a method of treatingretinopathy or other small vessel diseases associated with diabetesmellitus in a human while avoiding the concomitant liability of tumorpromotion associated with the administration of loratadine and othernon-sedating antihistamines, which comprises administering to said humana therapeutically effective amount of DCL or a pharmaceuticallyacceptable salt thereof.

Because DCL is much less active than loratadine at promoting tumors, afurther aspect of this invention is a method of treating allergicrhinitis in a human wherein said human has a higher than normalpropensity for or incidence of cancer, which comprises administering tosaid human a therapeutically effective amount of DCL or apharmaceutically acceptable salt thereof.

The present invention further encompasses a method of treating allergicasthma in a human wherein said human has a higher than normal propensityfor or incidence of cancer, which comprises administering to said humana therapeutically effective amount of DCL or a pharmaceuticallyacceptable salt thereof.

Also included in the present invention is a method for treatingretinopathy or other small vessel diseases associated with diabetesmellitus in a human wherein said human has a higher than normalpropensity for or incidence of cancer, which comprises administering tosaid human a therapeutically effective amount of DCL or apharmaceutically acceptable salt thereof.

Furthermore, the present invention also includes a method of treatingcough, cold, cold-like, and/or and flu symptoms and the discomfort,headache, pain, fever and general malaise associated therewith, in ahuman, wherein said human has a higher than normal propensity for orincidence of cancer, which comprises administering to said human acomposition, said composition comprising (i) a therapeutically effectiveamount of DCL or a pharmaceutically acceptable salt thereof, and (ii) atherapeutically effective amount of a non-steroidal antiinflammatoryagent or non-narcotic analgesic such as acetylsalicylic acid,acetaminophen, ibuprofen, ketoprofen, and naproxen, or apharmaceutically acceptable salt thereof.

Moreover, the present invention further encompasses a method of treatingcough, cold, cold-like and/or flu symptoms and the discomfort, headache,pain, fever and general malaise associated therewith, in a human,wherein said human has a higher than normal propensity for or incidenceof cancer, which comprises administering to said human a composition,said composition comprising (i) a therapeutically effective amount ofDCL or a pharmaceutically acceptable salt thereof, and (ii) atherapeutically effective amount of a decongestant such aspseudoephedrine or a pharmaceutically acceptable salt thereof.

It has also been found that when DCL is concurrently administered with adrug that inhibits cytochrome P450 including but not limited toketoconazole, itraconazole, erythromycin and others known by thoseskilled in the art, the interaction between said DCL and said drug isdecreased in comparison to the concurrent administration of loratadineor other non-sedating antihistamines with said drug.

Therefore, this invention also encompasses a method of avoidinginteraction between DCL and a drug that inhibits cytochrome P450including but not limited to ketoconazole, itraconazole, erythromycinand others known by those skilled in the art, while treating allergicrhinitis in a human, wherein said human is administered DCL or apharmaceutically acceptable salt thereof.

Moreover, this invention also encompasses a method of avoidinginteraction between loratadine or other non-sedating antihistamines anda drug that inhibits cytochrome P450 including but not limited toketoconazole, itraconazole, erythromycin and others known by thoseskilled in the art, while treating allergic asthma in a human, whereinsaid human is administered DCL or a pharmaceutically acceptable saltthereof.

This invention also encompasses a method of avoiding interaction betweenDCL and a drug that inhibits cytochrome P450 including but not limitedto ketoconazole, itraconazole, erythromycin and others known by thoseskilled in the art, while treating retinopathy or other small vesseldiseases associated with diabetes mellitus in a human, wherein saidhuman is administered DCL or a pharmaceutically acceptable salt thereof.

Also encompassed by the present invention is a method of avoidinginteraction between DCL and a drug that inhibits cytochrome P450including but not limited to ketoconazole, itraconazole, erythromycinand others known by those skilled in the art, while treating cough,cold, cold-like, and/or flu symptoms and the discomfort, headache, pain,fever and general malaise associated therewith, in a human, whichcomprises administering to said human a composition, said compositioncomprising (i) a therapeutically effective amount of DCL or apharmaceutically acceptable salt thereof, and (ii) a therapeuticallyeffective amount of a non-steroidal antiinflammatory agent ornon-narcotic analgesic, such as acetylsalicylic acid, acetaminophen,ibuprofen, ketoprofen, and naproxen, or a pharmaceutically acceptablesalt thereof.

A further aspect of the invention is a method of avoiding interactionbetween DCL and a drug that inhibits cytochrome P450 including but notlimited to ketoconazole, itraconazole, erythromycin and others known bythose skilled in the art, while treating cough, cold, cold-like, and/orflu symptoms and the discomfort, headache, pain, fever and generalmalaise associated therewith, in a human, which comprises administeringto said human a composition, said composition comprising (i) atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof, and (ii) a therapeutically effective amount of adecongestant such as pseudoephedrine or a pharmaceutically acceptablesalt thereof.

A further aspect of this invention includes a method of treatingurticaria in a human while avoiding the concomitant liability of adverseside-effects associated with the administration of non-sedatingantihistamines, comprising administering to said human a therapeuticallyeffective amount of DCL or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention includes a method of treatingsymptomatic dermographism in a human while avoiding the concomitantliability of adverse side-effects associated with the administration ofnon-sedating antihistamines, comprising administering to said human atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof.

It has also now been found that DCL is at least about twenty times morepotent at the histamine receptor when compared to loratadine. Thus, thedosage range by the modes of administration described herein and for usein the methods of the present invention, are about 0.1 to less thanabout 10 mg per day. This is significantly lower than what has beenrecommended for other non-sedating antihistamines, including loratadinewhich has a recommended oral dose of 5 to 100 mg per day. However, dueto the significantly less side-effects, DCL can be given in doses higherthan those suggested for loratadine thereby offering an improvedtherapeutic range than loratadine.

Loratadine and other non-sedating antihistamines have antihistaminicactivity and provide therapy and a reduction of symptoms for a varietyof conditions and disorders related to allergic rhinitis and otherallergic disorders, diabetes mellitus and other conditions; however,such drugs, while offering the expectation of efficacy, causes adverseside-effects. Utilizing DCL results in clearer dose-related definitionsof efficacy, diminished adverse side-effects, and accordingly, animproved therapeutic index. It is, therefore, more desirable to use DCLthan to use loratadine itself or other non-sedating antihistamines.

The term “adverse effects” includes, but is not limited to cardiacarrhythmias, cardiac conduction disturbances, appetite stimulation,weight gain, sedation, gastrointestinal distress, headache, dry mouth,constipation, and diarrhea. The term “cardiac arrhythmias” includes, butis not limited to ventricular tachyarrhythmias, torsades de pointes, andventricular fibrillation.

The phrase “therapeutically effective amount” means that amount of DCLwhich provides a therapeutic benefit in the treatment or management ofallergic rhinitis and other allergic disorders such as urticaria,symptomatic dermographism, allergic asthma, retinopathy or other smallvessel disorders associated with diabetes mellitus, and the symptomsassociated with allergic rhinitis such as cough, cold, cold-like, and/orflu symptoms including, but not limited to, sneezing, rhinorrhea,lacrimation, and dermal irritation.

The term “allergic asthma” is defined as a disorder characterized byincreased responsiveness of the trachea and bronchi to various stimuliwhich results in symptoms which include wheezing, cough, and dyspnea.

The term “diabetic retinopathy” or “retinopathy associated with diabetesmellitus” is that disorder caused by increased permeability of thecapillaries in the eye which leads to hemorrhages and edema in the eyeand can lead to blindness. The term “small vessel disorders associatedwith diabetes mellitus” includes, but is not limited to, diabeticretinopathy and peripheral vascular disease.

The magnitude of a prophylactic or therapeutic dose of DCL in the acuteor chronic management of disease will vary with the severity of thecondition to be treated and the route of administration. The dose, andperhaps the dose frequency, will also vary according to the age, bodyweight, and response of the individual patient. In general, the totaldaily dose range, for the conditions described herein, is from about 0.1mg to less than about 10 mg administered in single or divided dosesorally, topically, transdermally, or locally by inhalation. For example,a preferred oral daily dose range should be from about 0.1 mg to about 5mg. A more preferred oral dose is about 0.2 mg to about 1 mg.

It is further recommended that children, patients aged over 65 years,and those with impaired renal or hepatic function initially receive lowdoses, and that they then be titrated based on individual response(s) orblood level(s). It may be necessary to use dosages outside these rangesin some cases as will be apparent to those skilled in the art. Further,it is noted that the clinician or treating physician will know how andwhen to interrupt, adjust, or terminate therapy in conjunction withindividual patient response.

The term “therapeutically effective amount of DCL or a pharmaceuticallyacceptable salt thereof” is encompassed by the above-described dosageamounts. In addition, the terms “said composition comprising (i) atherapeutically effective amount of DCL or a pharmaceutically acceptablesalt thereof, and (ii) a therapeutically effective amount of at leastone non-steroidal antiinflammatory agent or non-narcotic or apharmaceutically acceptable salt thereof”; and “said compositioncomprising (i) a therapeutically effective amount of DCL or apharmaceutically acceptable salt thereof, and (ii) a therapeuticallyeffective amount of a decongestant such as pseudoephedrine or apharmaceutically acceptable salt thereof” are also encompassed by theabove-described dosage amounts and dose frequency schedule.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of DCL according to the methods of thepresent invention. For example, oral, rectal, parenteral, transdermal,subcutaneous, intramuscular, and like forms of administration may beemployed. Dosage forms include tablets, troches, dispersions,suspensions, solutions, capsules, patches, and the like.

The pharmaceutical compositions used in the methods of the presentinvention comprise DCL, the metabolic derivative of loratadine, asactive ingredient, or a pharmaceutically acceptable salt thereof, andmay also contain a pharmaceutically acceptable carrier, and optionally,other therapeutic ingredients.

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids or bases or organic acids or bases. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, andphosphoric. Appropriate organic acids may be selected, for example, fromaliphatic, aromatic, carboxylic and sulfonic classes of organic acids,examples of which are formic, acetic, propionic, succinic, glycolic,glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic,ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic,algenic, and galacturonic. Examples of such inorganic bases includemetallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium, and zinc. Appropriate organic bases may be selected,for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysineand procaine.

The compositions for use in the methods of the present invention includecompositions such as suspensions, solutions and elixirs; aerosols; orcarriers such as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike, in the case of oral solid preparations (such as powders, capsules,and tablets), with the oral solid preparations being preferred over theoral liquid preparations. The most preferred oral solid preparations aretablets.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compound foruse in the methods of the present invention may also be administered bycontrolled release means and/or delivery devices such as those describedin U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, the disclosures of which are hereby incorporated byreference.

Pharmaceutical compositions for use in the methods of the presentinvention suitable for oral administration may be presented as discreteunits such as capsules, cachets, or tablets, or aerosol sprays, eachcontaining a predetermined amount of the active ingredient, as a powderor granules, or as a solution or a suspension in an aqueous liquid, anon-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquidemulsion. Such compositions may be prepared by any of the methods ofpharmacy, but all methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally, with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet-contains, from about 0.1 mg toless than about 10 mg of the active ingredient, and each cachet orcapsule contains from about 0.1 mg to about less than 10 mg of theactive ingredient, i.e., DCL.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of the compound and thecompositions used in the methods of the present invention, as well astheir utility. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced which arewithin the scope of this invention.

4. EXAMPLES 4.1 Example 1 Preparation of Loratadine and its Metabolites

Loratadine can be synthesized by methods disclosed in U.S. Pat. No.4,282,233. The metabolites are prepared similarly, by reaction stepsconventional in the art, as described in U.S. Pat. No. 4,659,716 whichis incorporated here by reference in its entirety. One common method ofpreparing DCL is to reflux loratadine in the presence of sodiumhydroxide and ethanol as depicted below.

Extraction of Commercially Available Claritin Tablets (600×10 mg):

Tablets of loratadine, were diluted with water and chloroform. Themixture was stirred, then filtered through celite, rinsed withchloroform until the filtrate contained no loratadine. The separatedaqueous layer was extracted with chloroform twice. The combined organiclayer was washed with water, brine and dried over sodium sulfate. Thesolvent was evaporated to give pure loratadine as a white solid.

Saponification of Loratadine:

Loratadine (4.0 g) was added to a solution of sodium hydroxide (5.9 g)in 280 mL of absolute ethanol and the mixture was stirred at reflux forfour days. The mixture was cooled and concentrated to remove ethanol.The residue was diluted with water and aqueous layer was extracted withmethylene chloride five times. The combined organic layer was washedwith water, brine and dried over sodium sulfate. The solvent wasevaporated to give 2.82 g (87%) of pure loratadine derivative (ormetabolite) as a pale-tan solid.

4.2 Example 2

Antihistaminic Activity

The antihistaminic activity of loratadine and DCL were compared inisolated strips of guinea pig ileum contracted with histamine. Thispreparation is generally accepted by those skilled in the art aspredicative of its efficacy as a peripheral histamine H-1 receptor.

Methods:

Experiments were performed on pieces of ileum taken from male guineapigs (Hartley strain, 419–560 grams; Elm Hill Breeding Laboratories,Chelmsford, Mass.). The tissues were suspended in tissue chamberscontaining 40 ml of Tyrode's solution aerated with 95% oxygen and 5%carbon dioxide at 35° C. The Tyrode's solution contained (in mM) 137NaCl, 2.7 KCl, 2.2 CaCl₂, 0.025 MgCl₂, 0.4 NaHPO₄, 11.9 NaHCO₃ and 5.5glucose. Contractions in response to histamine were recorded withisotonic transducers (Model 357, Harvard Apparatus Company, SouthNatick, Mass.) using an ink-writing polygraph (Model 7, Grass InstrumentCompany, Quincy, Mass.). A tension of one gram was maintained on alltissues at all times.

In each experiment three or four pieces of ileum were removed from asingle animal, suspended in individual tissue chambers and allowed toequilibrate with the bathing solution for one hour before theadministration of any drugs. In four initial experiments in whichtissues were exposed to histamine at concentrations of 1×10⁻⁷, 1×10⁻⁶and 1×10⁻⁵ mol/l, histamine at 1×10⁻⁶ mol/l produced strong contractionson the linear portion of the log-concentration-effect curve and thisconcentration of histamine was chosen for use in all furtherexperiments.

For determining the antihistaminic effects of loratadine and DCL,tissues were exposed briefly (about 15 seconds) to 1×10⁻⁶ mol/l ofhistamine at intervals of 15 minutes. After two successive exposures tohistamine produced contractions of approximately the same magnitude,loratadine or DCL, at final concentrations that varied three- orten-fold, was added to all but one of the tissue chambers, the untreatedtissue serving as a control for the treated tissues. After each exposureof drug-treated tissues to histamine, the fluid in the tissue chamberwas replaced with fluid free of histamine but containing the same drugat the same concentration. The histamine challenges were made at 5, 20,35, 50, 65, 80, 95, 110 and 125 minutes of exposure to the drug or atcomparable times in the control tissues.

Subsequent analyses of the results from each experiment involved (i)normalization of the data from each tissue for differences in inherentcontractility by expressing all contractions as a percent of the lastpredug contraction, (ii) normalization of the data for possibletime-related changes in contractility by expressing the contractionsrecorded during drug-exposure as a percent of the corresponding valuefor the untreated tissue, and finally (iii) calculation of thedrug-related percent reduction of each contraction.

The resultant sets of data for drug concentration and correspondingpercent reduction in histamine-response were then used to estimate foreach experiment the concentration of drug that would have produced a 50percent reduction in the histamine response, the IC₅₀. This was done byfitting straight lines to the data using the method of least squares andcalculating the IC₅₀ from the equation of the line. The mean+/−standarderror of the values for the experiments on each drug were calculated,and differences between the drugs was examined using the Kruskal Wallis1-way analysis of variance by ranks.

A summary of the results are shown in the following two tables. Thepercentages of reduction of histamine-induced contractions of theisolated guinea pig ileum produced by exposure for 125 minutes tovarious concentrations of each drug are set forth below:

TABLE 1 Reduction of Histamine-induced Guinea Pig Ileum Contractions(Percent) Expt Concentration of drug (mol/1) Drug No. 3 × 10⁻¹⁰ 1 × 10⁻⁹3 × 10⁻⁹ 1 × 10⁻⁸ 3 × 10⁻⁸ 1 × 10⁻⁷ Loratadine 1 — 19.05 — 13.33 — 88.572 — — — 28.32 54.42 98.66 3 — — — 39.64 44.68 93.38 4 — — — 55.86 45.8386.46 DCL 1 11.93 73.12 2 38.91 38.81 56.71 3 40.00 62.69 76.21 4 35.4344.13 76.43

TABLE 2 Reduction of Histamine-induced Guinea Pig Icum Contractions(IC₅₀) Drug Expt IC₅₀(M) Loratadine 1 1.90 × 10⁻⁸ 2 2.21 × 10⁻⁸ 3 2.10 ×10⁻⁸ 4 1.22 × 10⁻⁸ Mean 1.86 × 10⁻⁸ S.E. 0.22 DCL 1 6.36 × 10⁻¹⁰ 2 19.2× 10⁻¹⁰ 3 5.26 × 10⁻¹⁰ 4 8.66 × 10⁻¹⁰ Mean 9.75 × 10⁻¹⁰ S.E. 3.20 Note:There is a statistically significant drug-related difference in IC₅₀values (P = 0.0209).

These results indicate that DCL is approximately 20 fold more potent atthe histamine receptor than loratadine.

4.3 Example 3

Receptor Binding Studies

Receptor binding studies on the binding affinities of loratadine and DCLat histamine H-1 receptors were performed.

The methods described by Dini et al., which is hereby incorporated byreference herein (Agents and Actions, 33:181–184, 1991), were used forthese binding studies. Guinea pig cerebella membranes were incubatedwith 0.5 nM 3H-pyrilamine for 10 min at 25° C. Following incubation, theassays were rapidly filtered under vacuum through GF/B glass fiberfilters (Whatman) and washed several times with ice-cold buffer using aBrandel Cell Harvester. Bound radioactivity was determined with a liquidscintillation counter (LS 6000, Beckman) using a liquid scintillationcocktail (Formula 989, DuPont NEN).

IC₅₀ values were determined for compounds tested and pyrilamine at theH-1 histamine receptor:

TABLE 3 Inhibition of Pyrilamine Binding at H-1 Receptor H-1 receptorCompound IC₅₀(nM) (nH) Loratadine 721   (1.55) DCL 51.1 (1.12)Pyrilamine  1.4 (0.98)

As shown above, DCL was found to have a 14 fold greater affinity thanloratadine for histamine H-1 receptors. These results are consistentwith the findings demonstrating a higher potency of DCL over loratadinefor inhibition of histamine-induced contractions of guinea pig ileum.

These studies confirm that DCL has a higher potency for histaminereceptors than loratadine.

4.4 Example 4

Tumor Promoting Activity

Inhibition of lymphocyte mitogenesis was used to screen the potencies ofloratadine and DCL as tumor promoting agents.

Mitogenesis Studies:

Fresh spleen cells (5×10⁵) obtained from 5-week old BALB/c mice (CharlesRiver, ST. Constant, PQ) were suspended in RPMI 1640 medium containing2% fetal calf serum (Grand Island Biological Co., Grand Island, N.Y.)seeded into replicate microwell plates (Nunc) to which concanavalin(Con) A (2 μg/ml; Sigma Chemical Co., St. Louis, Mo.) was added andincubated (37° C., 95% air, 5% CO₂) in the absence or presence ofincreasing concentrations of the test agents dissolved in saline orother vehicles. Forty-three hours after the addition of Con A, 0.25 nmol³H-thymidine (6.7 Ci/nmol; ICN Radiopharmaceuticals, Montreal, PQ) wasadded to each well. After an additional 5-hour incubation, the cellswere washed from the wells onto filter papers employing an automatedcell sorter. The filters were placed into vials containing 5 mlscintillation fluid (Readysafe; Beckman), and radioactivity incorporatedinto DNA at 48 hours was determined (n=3). IC₅₀ values for inhibition ofmitogenesis were determined over wide range of concentrations (0.1 to 10μM).

TABLE 4 Inhibition of Concanavalin A Induced Stimulation of Lymphocytes(IC₅₀) Loratadine 1.0 μM DCL 5.6 μM

These results indicate that DCL is 5–7 fold less active than loratadineat promoting tumor growth.

4.5 Example 5

Cardiovascular Effects

The effects of DCL on cardiac potassium currents were studied.

Methods:

Single ventricular myocytes of the guinea-pig and the rabbit weredissociated by enzymatic dispersion (see Carmeliet, J. Pharmacol. Exper.Ther., 1992, 262, 809–817 which is incorporated herein by reference inits entirety). The single suction patch electrode, with a resistance of2 to 5 MΩ was used for voltage clamp (Axoclamp 200A). P-clamp software(Axon Instruments) was used to generate voltage-clamp protocols and torecord and analyze data. The standard solution contained in mM: NaCl137.6, KCl 5.4, CaCl₂ 1.8, MgCl₂ 0.5, HEPES 11.6 and glucose 5, and NaOHwas added to pH 7.4. The intracellular solution contained KCl 120, MgCl₂6, CaCl₂ 0.154, Na₂ATP 5, EGTA 5, and HEPES 10, with KOH added until pH7.2.

Effect on the Delayed Rectifying K⁺ current, (I_(kr)) in RabbitVentricular Myocytes:

The voltage clamp protocol consisted of clamps from a holding potentialof −50 mV to +10 mV for a duration of 4 sec. The change in tail currentwas measured as a function of the drug concentration. This concentrationwas changed between 10⁻⁷ and 10⁻⁵ M in five steps. Exposure to eachconcentration lasted 15 min. At the end, washout was attempted during 30min.

Effect on the Inward Rectifier Current in Guinea-Pig Myocytes:

The inward rectifier was measured by applying ramp voltage clampsstarting from −50 mV and hyperpolarizing the membrane to −120 mV at aspeed of 10 mV/sec. The starting concentration was the 50% efficiencyconcentration, determined in the preceding experiments. Higherconcentrations were applied if this initial concentration was withouteffect.

Effect on IK_(s) in guinea-pig ventricular myocytes:

Tail currents were measured following depolarizing clamps of 2 secduration to potentials between −30 mV and +60 mV; holding potential −50mV.

The results from these studies indicate that DCL is less active thanterfenadine in inhibiting the cardiac delayed rectifier and thus has nopotential for cardiac side-effects. Thus, the methods of the presentinvention are less toxic than methods which use other non-sedatingantihistamines.

4.6 Example 6

Inhibition of Cytochrome P450

This study is conducted to determine the extent that loratadine and DCLinhibit human cytochrome P4503A4 (CYP3A4). CYP3A4 is involved in manydrug—drug interactions and quantitation of inhibition of CYP3A4 byloratadine or DCL indicates the potential of such drug—druginteractions. Inhibition is measured using the model substratetestosterone and cDNA-derived CYP3A4 in microsomes prepared from a humanlymphoblastoid cell line designated h3A4v3.

Study Design:

The inhibition study consists of the determination of the 50% inhibitoryconcentration (IC₅₀) for the test substance. A single testosteroneconcentration (120 μM, approximately twice the apparent Km) and ten testsubstance concentrations, separated by approximately ½ log, are testedin duplicate. Testosterone metabolism is assayed by the production ofthe 6(β)-hydroxytestosterone metabolite. This metabolite is readilyquantitated via HPLC separation with absorbance detection.

Storage/Preparation of the Test Substances and Addition to theIncubations:

The test substances will be stored at room temperature. The testsubstances will be dissolved in ethanol for addition to the incubations.The solvent concentration will be constant for all concentrations of thetest substance.

IC₅₀ Determination:

Final test substance concentrations will be 100, 30, 10, 3, 1, 0.3, 0.1,0.03, 0.01, 0.003 and 0 μM. Each test concentration will be tested induplicate incubations in accordance with the method below:

Method:

A 0.5 ml reaction mixture containing 0.7 mg/ml protein, 1.3 mM NADP+,3.3 mM glucose-6-phosphate, 0.4 U/ml glucose-6-phosphate dehydrogenase,3.3 mM magnesium chloride and 120 μM testosterone in 100 mM potassiumphosphate (pH 7.4) will be incubated at 37° C. for 30 min. A knownquantity of 11(β)-hydroxytestosterone will be added as an internalstandard to correct for recovery during extraction. The reaction mixturewill be extracted with 1 ml methylene chloride. The extract will bedried over anhydrous magnesium sulfate and evaporated under vacuum. Thesample will be dissolved in methanol and injected into a 4.6×250 mm 5uC18 HPLC column and separated at 50° C. with a mobile phasemethanol/water at a flow rate of 1 ml per min. The retention times areapproximately 6 min for the 6(β)-hydroxy, 8 min for 11(˜)-hydroxy and 12min for testosterone. The product and internal standard are detected bytheir absorbance at 254 nm and quantitated by correcting for theextraction efficiency using the absorbance of the 11(β)-hydroxy peak andcomparing to the absorbance of a standard curve for6(β)-hydroxytestosterone.

Data Reporting:

For each test substance, the concentration of 6(β)-hydroxytestosteronemetabolite in each replicate incubation is determined and the percentageinhibition relative to solvent control is calculated. The IC₅₀ iscalculated by linear interpolation.

Useful pharmaceutical dosage forms for administration of the compoundsused in the methods of the present invention can be illustrated asfollows:

4.7. Example 7

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 0.1 to 10 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

4.8. Example 8

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,lecithin, cottonseed oil or olive oil is prepared and injected by meansof a positive displacement pump into gelatin to form soft gelatincapsules containing 0.1 to 10 milligrams of the active ingredient. Thecapsules are washed and dried.

4.9 Example 9

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 0.1 to 10 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

Various modifications of the invention in addition to those shown anddescribed herein will be apparent to those skilled in the art from theforegoing description. Such modifications are also intended to fallwithin the scope of the appended claims.

The foregoing disclosure includes all the information deemed essentialto enable those skilled in the art to practice the claimed invention.Because the cited patents or publications may provide further usefulinformation these cited materials are hereby incorporated by referencein their entireties.

1. A pharmaceutical composition which comprises 0.1 to 10 mg ofdescarboethoxyloratadine, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 2. The pharmaceuticalcomposition of claim 1, which is adapted for oral administration.
 3. Thepharmaceutical composition of claim 1, which is solid.
 4. Thepharmaceutical composition of claim 3, which is in the form of capsuleor tablet.
 5. The pharmaceutical composition of claim 1, wherein thecarrier is selected from the group consisting of microcrystallinecellulose, starch, silicon dioxide, magnesium stearate, lactose, and acombination thereof.
 6. The pharmaceutical composition of claim 5,wherein the carrier comprises microcrystalline cellulose.
 7. Thepharmaceutical composition of claim 5, wherein the carrier comprisesstarch.
 8. The pharmaceutical composition of claim 5, wherein thecarrier comprises silicon dioxide.
 9. The pharmaceutical composition ofclaim 5, wherein the carrier comprises magnesium stearate.
 10. Thepharmaceutical composition of claim 5, wherein the carrier compriseslactose.
 11. A pharmaceutical composition comprising: a) 0.1 mg to 10 mgdescarboethoxyloratadine, or a pharmaceutically acceptable salt thereof;b) microcrystalline cellulose; and c) starch.
 12. The pharmaceuticalcomposition of claim 11, which further comprises silicon dioxide.